PROJECT SUMMARY/ABSTRACT Hepatitis C Virus (HCV) infection is a common comorbidity in patients with chronic kidney disease (CKD) that leads to accelerated progression to end-stage renal disease. Because of the recent approval of all-oral, interferon (IFN)-free, direct-acting antiviral therapy (DAAs), HCV can now be cured in the majority who are treated. This proposal seeks to identify factors that determine CKD outcomes in patients treated with DAAs, and to investigate the effect of enhanced IFN activation that occurs after HCV eradication on kidney function. Aim 1 employs the Scalable Collaborative Infrastructure for a Learning Healthcare System (SCILHS) Network, an electronic health records network covering 12 healthcare systems, to examine a large, diverse cohort of 10,000 patients with HCV infection to (1) determine the effect of DAAs on eGFR decline over five years follow- up and (2) identify factors that predict which HCV-infected patients are likely to have progressive CKD despite treatment of HCV infection. Aim 2A proposes to recruit 40 patients with HCV and CKD undergoing DAA treatment to prospectively study the IFN-pathway to determine if monocyte chemoattractant protein 1 (MCP-1), a candidate marker of IFN-activation, predicts which patients will have progressive CKD and which will recover. Aim 2B examines patients who develop de novo immune-mediated kidney diseases (lupus-like immune complex glomerulonephritis and focal segmental glomerulosclerosis) after DAAs to determine if baseline and post-treatment IFN-stimulated genes and chemokines are increased in patients who develop autoimmunity. This K23 Mentored Patient-Oriented Research Career Development Award proposal seeks to explore the effect of HCV eradication and IFN activation on CKD progression, and to prepare Dr. Sise for a career as an independent translational researcher in academic medicine. Dr. Sise's clinical training is in internal medicine and nephrology, with prior Masters-level training in biostatistics and patient-oriented research. During the course of this career development award, she will be supported by her institution to devote 75% of her time to focus on developing this research plan and completing didactic and hands-on training in longitudinal data analysis and immunology through coursework and applied analytic experience. Dr. Sise will benefit from the guidance of her primary mentor, Dr. Raymond Chung, an international leader in basic, translational, and clinical studies of HCV and HIV, and her co-mentor Dr. Ravi Thadhani, an established clinical and translational CKD investigator. Her training will also be overseen by an advisory committee of senior scientists, Drs. Jules Dienstag, Steven Grinspoon, and Arthur Kim, with collective expertise in mechanisms of immune activation in HCV and HIV, biomarker research, and clinical trials. She will work in collaboration with Dr. Kenneth Mandl (SCILHS network PI), Dr. Sushrut Waikar (CKD biomarkers) and Dr. Yuchiao Chang (Statistician). Dr. Sise's goal is to become an independent clinician-investigator at an academic center with a research program focused on strategies to slow CKD progression.